The histamine H3 receptor was first described as a presynaptic autoreceptor in the central nervous system (CNS) (ARRANG, J.-M. et al., “Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor”, Nature, 1983, pp 832-837, vol. 302) controlling the synthesis and release of histamine. The histamine H3 receptor is primarily expressed in the mammalian central nervous system (CNS), with some minimal expression in peripheral tissues such as vascular smooth muscle.
Thus, several indications for histamine H3 antagonists and inverse agonists have been proposed based on animal pharmacology and other experiments with known histamine H3 antagonists (e.g. thioperamide). (See: KRAUSE, M., et al., “The Histamine H3 Receptor-A Target for New Drugs, Leurs, R., et al. (Editors), Elsevier, 1998, pp 175-196 and pp 197-222; MORISSET, S. et al., “High constitutive activity of native H3 receptors regulates histamine neurons in brain”, Nature, 2000, pp 860-864, vol. 408) These include conditions such as cognitive disorders, sleep disorders, psychiatric disorders, and other disorders.
For example, histamine H3 antagonists have been shown to have pharmacological activity relevant to several key symptoms of depression, including sleep disorders (e.g. sleep disturbances, fatigue, and lethargy) and cognitive difficulties (e.g. memory and concentration impairment), as described above. For reviews, see: BONAVENTURE, P. et al., “Histamine H3 receptor antagonists: From target identification to drug leads” Biochem. Pharm., 2007, pp 1084-1096, vol. 73; and LETAVIC, M. A. et al., “5 Recent Medicinal Chemistry of the Histamine H3 Receptor”, Prog. Med. Chem., 2006, pp 181-206, vol. 44. There remains a need for potent histamine H3 receptor modulators with desirable pharmaceutical properties.
Keith, J. M. et al., in US Patent Publication 2007/0281923-A1, published Dec. 6, 2007 disclose pyridyl amide compounds, methods of making them, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by the histamine H3 receptor.
Letavic, M., et al., in U.S. Patent Publication 2009/0131415 A1, published May 17, 2009 disclose cycloalkyloxy- and heterocycloalkyloxypyridine compounds, methods of making them, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by the histamine H3 receptor.